CN101822682A - Injectable drug combining cefotaxime and tazobactam with proportion of 6:1 - Google Patents
Injectable drug combining cefotaxime and tazobactam with proportion of 6:1 Download PDFInfo
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- CN101822682A CN101822682A CN 201010161623 CN201010161623A CN101822682A CN 101822682 A CN101822682 A CN 101822682A CN 201010161623 CN201010161623 CN 201010161623 CN 201010161623 A CN201010161623 A CN 201010161623A CN 101822682 A CN101822682 A CN 101822682A
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Abstract
The invention relates to an injectable drug combining cefotaxime and tazobactam. The optimal proportion of 6:1 of cefotaxime to tazobactam is obtained by comparing enzyme inhibition rates and minimal inhibitory concentration (MIC) values of different proportions of cefotaxime to tazobactam.
Description
1, technical field
The present invention relates to a kind of drug regimen composition formula that can treat product beta-lactamase (comprise and produce extended spectrum) strain infection.
2, technical background
Along with the long-term of penicillins is extensive use of, the problem of bacterial drug resistance has caused the common concern of medical circle.Previous studies show that, antibacterial is because they can produce beta-lactamase (the 2a type enzyme that produces as staphylococcus aureus etc.) for the drug resistance of penicillins, these enzyme hydrolyzable penicillins and make it deactivation.As far back as nineteen nineties Smith-Kline﹠amp; Beecham company just Development and Production the compound preparation of beta-lactamase inhibitor (clavulanate potassium) and penicillins (amoxicillin).At present, domestic existing several companies produce, as the powerful amoxicillin of Zhuhai federation, the An Qi of Nanjing first sign-basis pharmacy etc.
After nineteen eighty-three, the fastbacteria of third-generation cephalosporin was found in Europe, Resistant strain was increasing for over ten years.Studies show that antibacterial is because produced new enzyme---extended spectrum (ESBLs) to the drug resistance of third-generation cephalosporin.Li Jiatai etc. have reported the characteristic of the clinical separation extended spectrum of China in 1996, they all have significant hydrolysis to cefotaxime.Cefotaxime hydrolytic enzyme (CTX-M family enzyme) is a kind of main extended spectrum.
The medicine that can suppress beta-lactamase has clavulanic acid, sulbactam and Tazobactam Sodium (TZB), and is wherein best with the Tazobactam Sodium effect.Tazobactam Sodium not only can suppress ESBLs, also can suppress part I type beta-lactamase (as the AmpC enzyme).Japan TAIHO drugmaker carried out much studying (US PATENT NO 5,763,603) to the compound preparation of Tazobactam Sodium and beta-lactam antibiotic.The present Tazocin (compound preparation of Tazobactam Sodium and piperacillin) of the main courteous Lay of the compound preparation of listing company, the sulperazone of Pfizer (compound preparation of cefoperazone and sulbactam).The price of Tazocin and sulperazone is very expensive, and its antibacterial activity and cefotaxime/Tazobactam Sodium of the present invention (CTX/TZB) compound preparation (seeing Table 3) are suitable.Because Tazobactam Sodium not only can suppress ESBLs, also can suppress part I type beta-lactamase (as the AmpC enzyme), especially in China, cefotaxime hydrolytic enzyme (CTX-M family enzyme) is a kind of main extended spectrum.Therefore, cefotaxime/Tazobactam Sodium compound recipe has significant compatibility reasonability than other compound preparation of being made up of beta-lactam antibiotic and beta-lactamase inhibitor.
The objective of the invention is by research the beta-lactamase-producing strain, especially Tazobactam Sodium is to the research that presses down the enzyme rate of the ESBLs of hydrolysis twice cefotaxime ability, in conjunction with the research of the different formulations of cefotaxime and Tazobactam Sodium, filtered out a kind of optimization formula that is suitable for treating cefotaxime for inj/Tazobactam Sodium (CTX/TZB) compound preparation of beta-lactamase-producing strain (comprise and produce the extended spectrum bacterial strain) infection to the MIC value of producing the main bacterial strain of ESBLs.
The object of the present invention is achieved like this: a kind of medicinal composition for injections of being made up of cefotaxime and Tazobactam Sodium, the optimum ratio of cefotaxime and Tazobactam Sodium are 6: 1.
3, test data
In the process of the present invention, at first get colon bacillus (ATCC 35218) and Klebsiella pneumonia (ATCC 700603) is made bacteria suspension, ultrasonic, pulverizing, get supernatant after centrifugal and make the rough enzyme liquid of extended spectrum (ESBLs).Be test organisms with staphylococcus aureus (ATCC25923) again, adopt inhibition zone method to prepare CTX (cefotaxime) concentration-antibacterial circle diameter standard curve, the linear concentration range of having determined CTX is between 8-128mg/L.The rough enzyme liquid of extended spectrum (ESBLs) that will be not commensurability is total to temperature with the CTX that contains 128mg/L down at 37 ℃ then, tries to achieve the required rough enzyme liquid measure of extended spectrum (ESBLs) of whole hydrolysis CTX.At last that hydrolyzable doubling dose CTX (256mg/L) is the required rough enzyme liquid of extended spectrum (ESBLs) adds in the cefotaxime/Tazobactam Sodium compound recipe (keeping the CTX final concentration is 128mg/L) of different proportionings, measure the antibacterial circle diameter of the cefotaxime/Tazobactam Sodium compound recipe of different proportionings behind 37 ℃ of incubations, do the standard curve of blank (enzyme-added but do not add TZB) and CTX simultaneously, try to achieve the CTX surplus of each mixed thing behind 37 ℃ of incubations, and calculate and press down enzyme rate (table 1).Computational methods are as follows:
CTX percent hydrolysis %=(CTX measured-the CTX surplus originally)/CTX measured originally * and 100%
CTX percent hydrolysis * 100% when pressing down enzyme rate %=(CTX percent hydrolysis-CTX percent hydrolysis when blank)/blank
By table 1 as seen, the proportioning of CTX/TZB is 1: 1-6: in the time of between 1, active inhibition can reach more than 80% (the going up the twice that presses down the enzyme rate in the table) to ESBLs; The proportioning of CTX/TZB is 2: 1-6: in the time of between 1, active inhibition can reach 100% to ESBLs; The proportioning of CTX/TZB 8: 1 when above, to the active inhibition less than 30% of ESBLs.Therefore, the proportioning of CTX/TZB should not be lower than 6: 1, otherwise TZB is not enough to protect CTX to avoid the hydrolysis of extended spectrum; Otherwise the proportioning of CTX/TZB also needn't be above 1: 1.The proportioning that table 1 can draw CTX/TZB is 6: 1 o'clock, and it is best to press down the enzyme effect.
In addition, we have also measured the MIC value of the cefotaxime/Tazobactam Sodium (CTX/TZB) of different proportionings to main product ESBLs bacterial strain, see Table 2.By table 2 as seen, the proportioning of cefotaxime/Tazobactam Sodium (CTX/TZB) is 4: 1-8: in the time of between 1, the MIC value is all lower.Be that antibacterial effect is preferable.
In cefotaxime/Tazobactam Sodium (CTX/TZB) compound recipe, CTX is main antibacterials, and TZB brings into play synergistic as the inhibitor of the beta-lactamase of hydrolysis CTX.Based on this reason, the amount of Tazobactam Sodium in cefotaxime/Tazobactam Sodium (CTX/TZB) compound preparation, it is prerequisite to the hydrolysis of TCX that Ying Yineng is enough to suppress beta-lactamase.
Comprehensive above-mentioned result of study, for the main bacterial strain that produces ESBLs, the suitable proportion of cefotaxime/Tazobactam Sodium (CTX/TZB) should satisfy is being enough to suppress to possess this primary condition of stronger antibacterial activity again under the prerequisite of ESBLs.Therefore, best proportioning is 6: 1.This is to constitute important component part of the present invention.
CTX, TZB, CTX/TZB (6: 1), Tazocin (Tazobactam Sodium/piperacillin injection) and sulperazone (cefoperazone/sulbactam injection) relatively see Table 2 to the antibacterial activity of the clinical isolating common pathogen of 200 strains in recent years.The result shows that the antibacterial activity of CTX/TZB (6: 1) significantly is better than its component C TX and TZB, and similar substantially with sulperazone to Tazocin.The present invention has the suitability and the exploitation on the clinical therapeutics on the significant medical industry to be worth.
Table 1 Tazobactam Sodium presses down the enzyme rate to the ESBLs's of hydrolysis twice CTX ability
(CTX/TZB) of the different proportionings of table 2 is to the MIC value of main product ESBLs bacterial strain
Continuous table 2
Table 3 cefotaxime/Tazobactam Sodium CTX/TZB (6: 1) compares summary sheet with other medicines to the clinical isolating antibacterial activity of 200 strains
Remarks: 200 strain bacterial strains are respectively: Bacillus proteus (producing ESBL) 1 strain, Hafnia alvei (not producing ESBL) 2 strains, Hafnia alvei (producing ESBL) 1 strain, the abnormal bacillus of slope (producing ESBL) 1 strain, lattice higher-dimension bacterium (not producing ESBL) 1 strain, staphylococcus aureus (MSSA) 23 strains, staphylococcus aureus (MRSA) 18 strains, other staphylococcus * * 23 strains, Klebsiella pneumonia (not producing ESBL) 15 strains, Klebsiella pneumonia (producing ESBL) 7 strains, colon bacillus (not producing ESBL) 21 strains, escherichia coli (producing ESBL) 22 strains, acetic acid acinetobacter calcoaceticus (not producing ESBL) 9 strains, acetic acid acinetobacter calcoaceticus (producing ESBL) 5 strains, citrobacter (not producing ESBL) 8 strains, citrobacter (producing ESBL) 4 strains, bacillus cloacae (not producing ESBL) 5 strains, bacillus cloacae (producing ESBL) 4 strains, enterococcus faecalis 6 strains, streptococcus equinus 4 strains, Hemolytic streptococcus 4 strains, bacillus pyocyaneus (not producing ESBL) 4 strains, bacillus pyocyaneus (producing ESBL) 2 strains, clostridium perfringen (not producing ESBL) 3 strains, clostridium perfringen (producing ESBL) 1 strain, enterobacter agglomerans (not producing ESBL) 2 strains, enterobacter agglomerans (producing ESBL) 2 strains, Bacillus proteus (not producing ESBL) 2 strains.
4, implementation example
In order to describe the present invention better, our illustrative example at this.But this does not represent that mode described in the embodiment is to implement unique channel of the present invention.In addition, mention the kind of the pharmaceutic adjuvant of some among the embodiment, these pharmaceutic adjuvants select for use for those of ordinary skill in the pharmaceutical industry in common knowledge.Example 1 get 0.17g sodium-tazobactam and 1.0g cefotaxime sodium in the environment of 50% following relative humidity in a usual manner mixed preparing pack into during the dry sterilization peace cuts open; Can add pharmaceutic adjuvants such as an amount of cosolvent, antioxidant in the preparation process.Add the dissolving of 4 ml physiological salines before using.Example 2 get 0.34g sodium-tazobactam and 2.0g cefotaxime sodium in the environment of 50% following relative humidity in a usual manner mixed preparing pack into during the dry sterilization peace cuts open; Can add pharmaceutic adjuvants such as an amount of cosolvent, antioxidant in the preparation process.Add the dissolving of 4 ml physiological salines before using.
Claims (1)
1. contain the medicinal composition for injections prescription that cefotaxime and Tazobactam Sodium are formed, the best proportioning that it is characterized in that cefotaxime and Tazobactam Sodium is 6: 1.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125562A (en) * | 2011-04-20 | 2011-07-20 | 叶海 | Medicinal composition for injection for treating superbug |
| CN102949397A (en) * | 2012-11-20 | 2013-03-06 | 海南葫芦娃制药有限公司 | Cefotaxime sodium and tazobactam sodium preparation for injection and preparing method thereof |
| CN116808047A (en) * | 2022-03-22 | 2023-09-29 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof |
| CN116808048A (en) * | 2022-03-22 | 2023-09-29 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof |
| CN118078836A (en) * | 2024-03-13 | 2024-05-28 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof in urinary system infection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1341417A (en) * | 2001-06-05 | 2002-03-27 | 南京威望医药保健品有限公司 | Injection medicine composite presciption containing cefotaxime and tazolepatan |
| CN1425376A (en) * | 2002-08-14 | 2003-06-25 | 海南国瑞堂制药有限公司 | Sodium cefetaxime and sodium tazotactam compound preparation for injection |
| CN101592637A (en) * | 2008-05-28 | 2009-12-02 | 广州威尔曼新药开发中心有限公司 | A kind of detection method of new compound CTX sodium-tazobactam sodium |
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2010
- 2010-05-04 CN CN 201010161623 patent/CN101822682A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1341417A (en) * | 2001-06-05 | 2002-03-27 | 南京威望医药保健品有限公司 | Injection medicine composite presciption containing cefotaxime and tazolepatan |
| CN1425376A (en) * | 2002-08-14 | 2003-06-25 | 海南国瑞堂制药有限公司 | Sodium cefetaxime and sodium tazotactam compound preparation for injection |
| CN101592637A (en) * | 2008-05-28 | 2009-12-02 | 广州威尔曼新药开发中心有限公司 | A kind of detection method of new compound CTX sodium-tazobactam sodium |
Non-Patent Citations (1)
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| 《第九届全国药物和化学异物代谢学术会议论文集》 20091023 刘文芳等 注射用头孢噻肟钠他唑巴坦钠(6:1)在健康人体内的药代动力学研究 第263页 1 , 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125562A (en) * | 2011-04-20 | 2011-07-20 | 叶海 | Medicinal composition for injection for treating superbug |
| CN102125562B (en) * | 2011-04-20 | 2012-08-22 | 南京优科生物医药有限公司 | Medicinal composition for injection for treating superbug |
| CN102949397A (en) * | 2012-11-20 | 2013-03-06 | 海南葫芦娃制药有限公司 | Cefotaxime sodium and tazobactam sodium preparation for injection and preparing method thereof |
| CN102949397B (en) * | 2012-11-20 | 2014-05-14 | 海南葫芦娃制药有限公司 | Cefotaxime sodium and tazobactam sodium preparation for injection and preparing method thereof |
| CN116808047A (en) * | 2022-03-22 | 2023-09-29 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof |
| CN116808048A (en) * | 2022-03-22 | 2023-09-29 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof |
| CN118078836A (en) * | 2024-03-13 | 2024-05-28 | 南京优科生物医药股份有限公司 | Application of cefotaxime or salt thereof and tazobactam or salt thereof in urinary system infection |
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Open date: 20100908 |